Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Mitochondrial Damage and Inflammation by Stabilizing Mitochondrial DNA

Abstract

Mitochondrial dysfunction is a key feature of injury to numerous tissues and stem cell aging. Although the tissue regenerative role of mesenchymal stem cell (MSC)derived extracellular vesicles (MSC-EVs) is well known, their specific role in regulating mitochondrial function in target cells remains elusive. Here, we report that MSC-EVs attenuated mtDNA damage and inflammation after acute kidney injury (AKI) and that this effect was at least partially dependent on the mitochondrial transcription factor A (TFAM) pathway. In detail, TFAM and mtDNA were depleted by oxidative stress in MSCs from aged or diabetic donors. Higher levels of TFAM mRNA and mtDNA were detected in normal control (NC) MSC-EVs than in TFAM-knockdown (TFAM-KD) and aged EVs. EV-mediated TFAM mRNA transfer in recipient cells was unaffected by transcriptional inhibition. Accordingly, the application of MSC-EVs restored TFAM protein and TFAM-mtDNA complex (nucleoid) stability, thereby reversing mtDNA deletion and mitochondrial oxidative phosphorylation (OXPHOS) defects in injured renal tubular cells. Loss of TFAM also led to downregulation of multiple anti-inflammatory miRNAs and proteins in MSC-EVs. In vivo, intravenously injected EVs primarily accumulated in the liver, kidney, spleen, and lung. MSC-EVs attenuated renal lesion formation, mitochondrial damage, and inflammation in mice with AKI, whereas EVs from TFAM-KD or aged MSCs resulted in poor therapeutic outcomes. Moreover, TFAM overexpression (TFAM-OE) improved the rescue effect of MSC-EVs on mitochondrial damage and inflammation to some extent. This study suggests that MSC-EVs are promising nanotherapeutics for diseases characterized by mitochondrial damage, and TFAM signaling is essential for maintaining their regenerative capacity.

TBHQ Regulates the Nrf2/HO-1 Pathway to Enhance Stem Cell Treatment of Diabetic Retinopathy

“…In the present study, transplantation of hUCMSCs into the vitreous cavity resulted in signi cant inhibition of the retinal in ammatory response signi cant decrease in in ammatory factors such as IL-1β and NF-κB p65. This has also been found in other studies [56,57] . In general, high immunosuppression is a key characteristic of MSCs.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapeutic Strategy for Acute Kidney Injury

“…In addition to renal tubular cells, vascular endothelial cells are also damaged during AKI. The delivery of mitochondria from MSC-EVs reduced apoptosis and increased cell viability, and restored the normal balance between aerobic respiration and glycolysis, indicating the re-establishment of aerobic respiration (12,81). EVs derived from MSCs have previously demonstrated huge therapeutic potential in AKI via transporting proteins and RNAs with biological activity, and by conveying mitochondria and their DNA directly, suggesting that modifying the contents of MSC-EVs to affect specific signaling pathways may represent a promising therapeutic approach (28,85).…”

“…Mitochondria are considered to play an integral role in AKI development ( 80 ), suggesting the possibility that mitochondria might be transferred horizontally into kidney cells to reprogram cell metabolism and promote kidney recovery. Mitochondrial DNA or mitochondria can be transported directly into the damaged site by EVs, thus reducing kidney damage ( 81 ). Spees et al.…”

Intervertebral Disc Stem/Progenitor Cells: A Promising “Seed” for Intervertebral Disc Regeneration

“…Extracellular vesicles (EVs) are lipid membrane particles carrying proteins, lipids, DNA, and various types of RNA that are involved in intercellular communication. EVs derived from stem/progenitor cells have been suggested to be excellent therapeutic agents in many diseases, including IVDD [ 105 – 108 ]. Many different groups have demonstrated that MSC-derived EVs can inhibit apoptosis and promote the proliferation of the IVD cells.…”